DESCRIPTION: (Investigator's Abstract) Adenosine is a potent inhibitory modulator of synaptic transmission in the central nervous system. However, its functional role, particularly in normal brain activity, remains to be determined. The present experiments are aimed at defining this role, using electrophysiological techniques to study the effects of adenosine on neural activity in hippocampal slices form rat brain. The first set of experiments will investigate ways in which adenosine receptor sensitivity can be modulated by other adenosine receptors and by metabotropic glutamate receptors. Preliminary studies have shown that adenosine A3 receptor activation reduces adenosine A1 receptor sensitivity, and this process is hypothesized to underlie a variety of phenomena, such as the hyperexcitability protective effects of adenosine in hypoxia. Blocking the desensitization of A1 adenosine receptors via this mechanism may provide a way of enhancing some of the therapeutic actions of adenosine in brain ischemia and hypoxia. The other major focus will be on physiological events that produce transient changes in extracellular purine concentrations. These experiments will identify and study physiological stimuli which release adenosine or related purines, such as excitatory synaptic stimulation, NMDA receptor activation, activation of adenylyl cyclase, and hypoxia. These responses will be compared to those elicited by direct application of purines to agents to selectively affect responses to adenosine and to purine nucleotides will be investigated, and the interactions of these agents with physiologically stimulated release of purines will be characterized. The studies detailed in this proposal should provide insight into the ways in which adenosine receptors in the brain are activated under normal and pathological conditions, and how extracellular adenosine levels are regulated. Although adenosine receptor antagonists such as caffeine and theophylline have some therapeutic actions, thee are currently no neurological or psychiatric indications for the use adenosine receptor agonist. The basic information that will be learned from the proposed experiments about the role of adenosine in the nervous system might suggest possible clinical applications for these drugs.